Blumberg, B.S.

Feret, E.

Froment, Alain

Larouzé, B.

London, W.T.

Marinier, E.

Sow, A.M.

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References 
development of more sensitive detection methods, a close associatiòn was 
found [2, 7, IO]. The discrepancy between the earlier and later observations 
led to the realization that HBsAg was present at much lower concentrations 
in the sera of patients with PHC than in those of other persistently infected 
individuals. 
Our investigations in West Africa began in 1973 and continue to the 
present with the objective of testing the hypothesis that persistent infection 
with HBV is necessary for the development of PHC. The ultimate objective 
of our investigations is the development of strategies to prevent this neo- 
plasm. In 1969, Millman and Blumberg in our laboratory in Philadelphia 
described a process for making a vaccine for hepatitis B prepared from sur- 
136 
Blumberg, B.S.: Australia antigen and the biology of hepatitis B. Science I97: 17-25 
(1977); also the patent: Blumberg, B.S. and Millman, I.: Vaccine Against Viral 
Hepatitis and Process, U.S. Patent Office No. 3,636,191 (1972). 
Blumberg, B.S.; Larouzé, B.; London, W.T.; Werner, B.; Hesser, J.E.; Millman, I.; 
Saimot, G.; Payet, M.: The relation of infection with hepatitis B agent to primary 
hepatic carcinoma. Am. J. Path. 81: 669-682 (1975). 
Blumberg, B.S. ; Sutnick, A.I.; London, W.T. : Hepatitis and leukemia: their rela- 
tion to Australia antigen. Bull. N.Y. Acad. Med. 44: 1566-1586 (1968). 
Larouz6, B.; Blumberg, B.S.; London, W.T.; Lustbader, E.D.; Sankale, M.; Payet, 
M.: Forecasting the development of primary hepatocellular carcinoma by the use 
of risk factors: studies in West Africa. J. natn. Cancer Inst. 58: 1557-1561 (1977). 
Larouzé, B.; London, W.T.; Saimot, G.; Werner, B.G.; Lustbader, E.D.; Payet, M.; 
Blumberg, B.S.: Host responses to hepatitis B infection in patients with primary 
hepatic carcinoma and their families. A case/control study in Senegal, West Africa. 
Lancet ii: 534-538 (1976). 
Maupas, P.; Larouz6, B.; London, W.T.; Werner, B.; Millman, I.; O’Connell, A.; 
Blumberg, B.S.; Saimot, G.; Payet, M.: Antibody to hepatitis-B core antigen in 
patients with primary hepatic carcinoma. Lancet ii: 9-11 (1975). 
Nishioka, K.; Mayumi, M.; Okochi, K.; Okada, K.; Hirayama, T.: Natural history 
of Australia antigen and hepatocellular carcinoma; in Nakahara, Hirayama, Nishi- 
Oka, Sugano, Analytic and experimental epidemiology of cancer, pp. 137-146 
(University of .Tokyo Press, Tokyo 1973). 
Ohbayashi, A.; Okochi, K.; Mayumi, M. : Familial clustering of asymptomatic 
carriers of Australia antigen and patients with chronic liver disease or primary liver 
cancer. Gastroenterology 62: 618-625 (1972). 
Smith, J.B. ; Blumberg, B.S. : Viral hepatitis, post-necrotic cirrhosis and hepato- 
cellular carcinoma. Lancet ii: 953 (1969). 
Vogel, C.; Anthony, P.; Sadikali, F.; Barker, L.F.; Peterson, M.R.: Hepatitis- 
associated antigen and antibody in hepatocellular carcinoma: results of a continuing 
study. J. natn. Cancer Inst. 48: 1583-1588 (1972). 
Werner, B.G.; Murphy, B.L.; Maynard, J.E.; Larouz6, B.: Anti-e in primary hepatic 
carcinoma. Lancet i: 696 (1976). 
I 
Progress in Medical Virology 
Editor: J.L. Melnick, Houston, Tex. 
Publishers : S .  Karger, Basel 
Reprint (Printed in Switzerland) 
Prog. med. Virol., vol. 27, pp. 133-136 (Karger, Basel 1981) 
Hepatitis B Infection and the Prevention of Primary 
Hepatocellular Carcinoma: Studies in Senegal’ 
.Alain Froment, Bernard Larouzt?, Elisabeth Feret, Evelyne Marinier, 
A. Moustapha Sow3, W. Thomas London and Baruch S. Blumberg 
The Institute for Cancer Research, The Fox Chase Cancer Center, Philadelphia, 
Pa., USA, Institut Léon M’Ba, HGpital Claude Bernard, Paris, Francez, and 
Clinique Médicale, Faculté de MBdecine, Dakar, Senegal, West Africa8 
1 This work was supported by USPHS grants CA-06551, RR-05539 and CA-O6927 
from the National Institutes of Health and by an appropriation from the Commonwealth 
()@TOM Fondsi Documentaire 
Dr. Baruch S. Blumberg, The Institute for Cancer Research, 
The Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111 (USA? 
r Froment/Larouzé/Feret/Marinier/Sow/London/Blum berg 134 HBV Infection and Prevention of PHC in Senegal 135 
with infection acquired from carrier mothers. In a study of family members 
of 27 PHC cases, we found that 70% of mothers of patients with PHC were 
HBsAg(-t) compared with 14% of mothers of controls [5]. Secondly, we 
tested the hypothesis that chronic liver diseases (primarily cirrhosis) which 
were known' to be associated with PHC were associated with persistent 
hepatitis B infection. This hypothesis was also supported. In Mali, we ob- 
served that in cases of chronic liver disease 46% were HBsAg( +) compared 
with 75% of PHC cases and 5% of controls [4]. . 
In the course of these studies, we investigated the association of anti- 
HBc with PHC. We reported in 1975 that anti-HBc was a more frequent 
indication of HBV infection than HBsAg in PHC patients; again proba- 
bly reflecting the low level of HBsAg in the sera of these patients. 90% 
of PHC cases in Senegal were anti-HBc(+) compared with 28% of con- 
trols [4, 61. 
We also examined the relationship of HBeAg and anti-HBe to PHC. 
Werner et al. [ll] showed that e antigen was rarely found in patients with 
PHC but anti-HBe was frequently present. This observation is consistent 
with the thesis that PHC occurs in individuals who have been infected with 
HBV for many years and that by the time their tumor becomes clinically 
evident, active viral replication has ceased. 
Our studies now in progress in Senegal are directed at four aspects of 
the interaction of HBV with humans and ultimately relate to the risk of 
developing PHC. 
a. Studies in other populations have shown variations by ethnic group 
in the frequency with which carrier mothers infect their infants. The fre- 
quency of mother-to-child infection, the age at which it occurs, and the type 
of response of infants to such infection are important variables in the de- 
velopment of strategies of prevention of hepatitis B infection and PHC. We 
are investigating mother-to-child transmission of hepatitis B in Thies, a 
town 70 km east of Dakar. About 2,000 women have had blood drawn at 
the time of delivery. Approximately 100 children born to HBsAg( -I-) women 
and 200 children born to HBsAg(-) women are being tested at the following 
intervals after birth: 15 days, 3 months, 6 months, 1 year, and annually 
thereafter for 3 years. 
b. Studies of whole communities over time permit evaluation of the 
impact of infection on the entire population, on family units within the 
community, and the age at which individuals in the community are most 
likely to become infected. We are focusing our investigation on the villages 
of the rural community of Tip, about 220 km east of Dakar. A census of 
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each village has been taken and family relationships identified. Blood samples 
have been collected annually for the past 3 years from about 80% of the 
population. This should be extremely useful in evaluating field trials of vac- 
cines and other control measures. 
c. We are continuing to study the families of patients with PHC and 
families of patients with cirrhosis or CAH. Blood samples have been collected 
from about 170 families of PHC cases and 80 families of cases of chronic 
liver disease. ,These studies will evaluate the role of mothers and fathers of 
PHC patients in the transmission of HBV and the type of response to infec- 
tion. Hepatitis B infection in siblings and children of cases is also being' 
assessed. 
d. Many of the areas of the world with high prevalences of chronic 
carriers of HBV are also areas where severe malnutrition may occur. We are 
studying the interaction of protein-calorie malnutrition (PCM) in Senegalese 
children with their responses to infection with HBV. 132 children with PCM 
treated in the Pediatric Clinic at Le Dantec Hospital in Dakar have been 
identified and are being compared with 134 children treated in the same 
clinic for other conditions. Blood samples have been obtained at diagnosis 
and 30 days after the initiation of therapy. 
Analysis of the data from these four studies is just beginning, but cer- 
tain interesting points are emerging. Before the age of 6 months, appearance 
of HBsAg in the serum of infants, born to HBsAg( +) women, appears to be 
a rare event. Anti-HBs transmitted from mother to child seems to have a 
limited protective effect. The studies in the Tip population suggest that the 
peak frequency of HBsAg positivity is in the 10- to 19-year age group. If this 
is confirmed, it suggests that the hepatitis B vaccine given early in life will 
probably protect most of the population from HBV infection. That is, even 
if perinatal mother-to-child transmission is not prevented by the vaccine, 
the overall incidence of hepatitis B infection in this population would be 
drastically reduced. 
Studies of malnourished children suggest that they become infected at 
an earlier age than well-nourished children and that they may have a dif- 
ferent response to this infection. This information will also bear on preven- 
tion strategies. The vaccine may be less effective in malnourished children or 
may have unforeseen consequences in such children. 
We believe that studies of the kind described above and similar studies 
on other populations in other parts of the world will, in due course, lead to 
effective methods for preventing hepatitis B infection and most cases of 
hepatocellular carcinoma in humans. 


Hepatitis B infection and the prevention of primary hepatocellular carcinoma : studies in Senegal

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